Patients with advanced cancer often have to be treated continuously for severe pain. Unfortunately, the narcotic analgesics used to obtund suffering frequently also obtund the patient's entire personality to the point of incapacitation. This project attempts to develop a method of interrupting nociception regionally by selectively blocking small caliber nerve fibers that signal pain, leaving large fibers that subserve touch and motor function unaffected. Success will open the way to lasting relief of cancer pain with little or no detriment to personality. Empirical, unsuccessful attempts at selective block go back more than forty years. Recent research by the applicant finds a new basis for lasting differential block in the energy requirements of mammalian nerve fibers: The requirements of unmyelinated fibers, in terms of ambient glucose and oxygen concentrations, are found to be much lower than those of large myelinated fibers, so that the supply of substrate can be manipulated to produce a sharply selective block of conduction in vitro. Although the block in this case selectively affects large fibers, the latest work indicates that the opposite, and desired, selectivity, durably blocking small fibers exclusively, may be attainable with the aid of certain inhibitors. The project will determine the identity, duration and mode of action, and optimal concentration of differential inhibitors, by measurements on the compound action potential of normal excised vagus nerves of rabbit and by observations on single units in the nodose ganglion. Experiments in rat will test the antinociceptive effectiveness of the inhibitors in vivo and correlate it with the local histological reaction observed by light and electron microscopy.